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Prions, prionoids and protein misfolding disorders

Nature Reviews Genetics volume 19, pages 405–418 (2018)Cite this article

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Abstract

Prion diseases are progressive, incurable and fatal neurodegenerative conditions. The term ‘prion’ was first nominated to express the revolutionary concept that a protein could be infectious. We now know that prions consist of PrPSc, the pathological aggregated form of the cellular prion protein PrPC. Over the years, the term has been semantically broadened to describe aggregates irrespective of their infectivity, and the prion concept is now being applied, perhaps overenthusiastically, to all neurodegenerative diseases that involve protein aggregation. Indeed, recent studies suggest that prion diseases (PrDs) and protein misfolding disorders (PMDs) share some common disease mechanisms, which could have implications for potential treatments. Nevertheless, the transmissibility of bona fide prions is unique, and PrDs should be considered as distinct from other PMDs.

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Fig. 1: The nucleation and fragmentation cycle of prions and prionoids.
Fig. 2: Structure of the prion protein and amino acid substitutions that have been linked to genetic prion diseases.
Fig. 3: Therapeutic approaches targeting protein aggregation.

References

  1. Brown, P., Cathala, F., Castaigne, P. & Gajdusek, D. C. Creutzfeldt-Jakob disease: clinical analysis of a consecutive series of 230 neuropathologically verified cases. Ann. Neurol. 20, 597–602 (1986).

    Article  PubMed  CAS  Google Scholar 

  2. Prusiner, S. B. Novel proteinaceous infectious particles cause scrapie. Science 216, 136–144 (1982). This paper introduces the term ‘prion’ to describe the revolutionary concept of protein-mediated transmissibility.

    Article  PubMed  CAS  Google Scholar 

  3. Bolton, D. C., McKinley, M. P. & Prusiner, S. B. Identification of a protein that purifies with the scrapie prion. Science 218, 1309–1311 (1982). This study demonstrates that prions contain an aggregated form of a cellular protein.

    Article  PubMed  CAS  Google Scholar 

  4. Büeler, H. et al. Mice devoid of PrP are resistant to scrapie. Cell 73, 1339–1347 (1993). This paper provides confirmation that PrP C is required for prion propagation and disease manifestation.

    Article  PubMed  Google Scholar 

  5. Jarrett, J. T. & Lansbury, P. T. Seeding ‘one-dimensional crystallization’ of amyloid: a pathogenic mechanism in Alzheimer’s disease and scrapie? Cell 73, 1055–1058 (1993).

    Article  PubMed  CAS  Google Scholar 

  6. Knowles, T. P. J. et al. An analytical solution to the kinetics of breakable filament assembly. Science 326, 1533–1537 (2009). This analytical approach describes how fragmentation-nucleation cycles contribute to aggregate propagation.

    Article  PubMed  CAS  Google Scholar 

  7. Cox, B., Ness, F. & Tuite, M. Analysis of the generation and segregation of propagons: entities that propagate the [PSI+] prion in yeast. Genetics 165, 23–33 (2003).

    PubMed  PubMed Central  CAS  Google Scholar 

  8. Aguzzi, A. & Lakkaraju, A. K. K. Cell biology of prions and prionoids: a status report. Trends Cell Biol. 26, 40–51 (2016).

    Article  PubMed  CAS  Google Scholar 

  9. Saborio, G. P., Permanne, B. & Soto, C. Sensitive detection of pathological prion protein by cyclic amplification of protein misfolding. Nature 411, 810–813 (2001).

    Article  PubMed  CAS  Google Scholar 

  10. Sailer, A., Büeler, H., Fischer, M., Aguzzi, A. & Weissmann, C. No propagation of prions in mice devoid of PrP. Cell 77, 967–968 (1994).

    Article  PubMed  CAS  Google Scholar 

  11. Brandner, S. et al. Normal host prion protein necessary for scrapie-induced neurotoxicity. Nature 379, 339–343 (1996). This paper demonstrates that aggregation and aggregation-induced toxicity can be uncoupled by chronically exposing PrP-deficient mice to prions.

    Article  PubMed  CAS  Google Scholar 

  12. Hu, P. P. et al. Role of prion replication in the strain-dependent brain regional distribution of prions. J. Biol. Chem. 291, 12880–12887 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Glatzel, M., Abela, E., Maissen, M. & Aguzzi, A. Extraneural pathologic prion protein in sporadic Creutzfeldt-Jakob disease. N. Engl. J. Med. 349, 1812–1820 (2003).

    Article  PubMed  CAS  Google Scholar 

  14. Aguzzi, A. Cell biology: beyond the prion principle. Nature 459, 924–925 (2009). This paper introduces the term ‘prionoid’ to describe aggregates that can spread between cells but for which transmissibility between individuals has not yet been demonstrated.

    Article  PubMed  CAS  Google Scholar 

  15. Aguzzi, A. & Rajendran, L. The transcellular spread of cytosolic amyloids, prions, and prionoids. Neuron 64, 783–790 (2009).

    Article  PubMed  CAS  Google Scholar 

  16. Bruce, M. E. et al. Transmissions to mice indicate that ‘new variant’ CJD is caused by the BSE agent. Nature 389, 498–501 (1997).

    Article  PubMed  CAS  Google Scholar 

  17. Wells, G. A. et al. A novel progressive spongiform encephalopathy in cattle. Vet. Rec. 121, 419–420 (1987).

    Article  PubMed  CAS  Google Scholar 

  18. Williams, E. S. & Young, S. Chronic wasting disease of captive mule deer: a spongiform encephalopathy. J. Wildl. Dis. 16, 89–98 (1980).

    Article  PubMed  CAS  Google Scholar 

  19. Aguzzi, A., Heikenwalder, M. & Polymenidou, M. Insights into prion strains and neurotoxicity. Nat. Rev. Mol. Cell. Biol. 8, 552–561 (2007).

    Article  PubMed  CAS  Google Scholar 

  20. Kretzschmar, H. A. et al. Molecular cloning of a human prion protein cDNA. DNA 5, 315–324 (1986).

    Article  PubMed  CAS  Google Scholar 

  21. Riek, R. et al. NMR structure of the mouse prion protein domain PrP(121–231). Nature 382, 180–182 (1996).

    Article  PubMed  CAS  Google Scholar 

  22. Wulf, M.-A., Senatore, A. & Aguzzi, A. The biological function of the cellular prion protein: an update. BMC Biol. 15, 34 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  23. Nuvolone, M. et al. Strictly co-isogenic C57BL/6 J-Prnp−/− mice: a rigorous resource for prion science. J. Exp. Med. 213, 313–327 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Nuvolone, M. et al. SIRPα polymorphisms, but not the prion protein, control phagocytosis of apoptotic cells. J. Exp. Med. 210, 2539–2552 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bremer, J. et al. Axonal prion protein is required for peripheral myelin maintenance. Nat. Neurosci. 13, 310–318 (2010).

    Article  PubMed  CAS  Google Scholar 

  26. Küffer, A. et al. The prion protein is an agonistic ligand of the G protein-coupled receptor Adgrg6. Nature 536, 464–468 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Hsiao, K. et al. Linkage of a prion protein missense variant to Gerstmann-Sträussler syndrome. Nature 338, 342–345 (1989).

    Article  PubMed  CAS  Google Scholar 

  28. Medori, R. et al. Fatal familial insomnia, a prion disease with a mutation at codon 178 of the prion protein gene. N. Engl. J. Med. 326, 444–449 (1992).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  29. Kretzschmar, H. A., Neumann, M. & Stavrou, D. Codon 178 mutation of the human prion protein gene in a German family (Backer family): sequencing data from 72-year-old celloidin-embedded brain tissue. Acta Neuropathol. 89, 96–98 (1995).

    Article  PubMed  CAS  Google Scholar 

  30. Apetri, A. C., Vanik, D. L. & Surewicz, W. K. Polymorphism at residue 129 modulates the conformational conversion of the D178N variant of human prion protein 90–231. Biochemistry 44, 15880–15888 (2005).

    Article  PubMed  CAS  Google Scholar 

  31. Hsiao, K. et al. Mutation of the prion protein in Libyan Jews with Creutzfeldt-Jakob disease. N. Engl. J. Med. 324, 1091–1097 (1991).

    Article  PubMed  CAS  Google Scholar 

  32. Pocchiari, M. et al. A new point mutation of the prion protein gene in Creutzfeldt-Jakob disease. Ann. Neurol. 34, 802–807 (1993).

    Article  PubMed  CAS  Google Scholar 

  33. Capellari, S., Strammiello, R., Saverioni, D., Kretzschmar, H. & Parchi, P. Genetic Creutzfeldt-Jakob disease and fatal familial insomnia: insights into phenotypic variability and disease pathogenesis. Acta Neuropathol. 121, 21–37 (2011).

    Article  PubMed  CAS  Google Scholar 

  34. Parchi, P. et al. Molecular basis of phenotypic variability in sporadic Creutzfeldt-Jakob disease. Ann. Neurol. 39, 767–778 (1996).

    Article  PubMed  CAS  Google Scholar 

  35. Palmer, M. S., Dryden, A. J., Hughes, J. T. & Collinge, J. Homozygous prion protein genotype predisposes to sporadic Creutzfeldt-Jakob disease. Nature 352, 340–342 (1991).

    Article  PubMed  CAS  Google Scholar 

  36. Nurmi, M. H. et al. The normal population distribution of PRNP codon 129 polymorphism. Acta Neurol. Scand. 108, 374–378 (2003).

    Article  PubMed  CAS  Google Scholar 

  37. Pocchiari, M. et al. Predictors of survival in sporadic Creutzfeldt-Jakob disease and other human transmissible spongiform encephalopathies. Brain 127, 2348–2359 (2004).

    Article  PubMed  CAS  Google Scholar 

  38. Mok, T. et al. Variant Creutzfeldt-Jakob disease in a patient with heterozygosity at PRNP codon 129. N. Engl. J. Med. 376, 292–294 (2017).

    Article  PubMed  Google Scholar 

  39. Llewelyn, C. A. et al. Possible transmission of variant Creutzfeldt-Jakob disease by blood transfusion. Lancet 363, 417–421 (2004).

    Article  PubMed  CAS  Google Scholar 

  40. Wroe, S. J. et al. Clinical presentation and pre-mortem diagnosis of variant Creutzfeldt-Jakob disease associated with blood transfusion: a case report. Lancet 368, 2061–2067 (2006).

    Article  PubMed  Google Scholar 

  41. Peden, A. H., Head, M. W., Ritchie, D. L., Bell, J. E. & Ironside, J. W. Preclinical vCJD after blood transfusion in a PRNP codon 129 heterozygous patient. Lancet 364, 527–529 (2004).

    Article  PubMed  Google Scholar 

  42. Mead, S. et al. A novel protective prion protein variant that colocalizes with kuru exposure. N. Engl. J. Med. 361, 2056–2065 (2009).

    Article  PubMed  CAS  Google Scholar 

  43. Shibuya, S., Higuchi, J., Shin, R. W., Tateishi, J. & Kitamoto, T. Protective prion protein polymorphisms against sporadic Creutzfeldt-Jakob disease. Lancet 351, 419 (1998).

    Article  PubMed  CAS  Google Scholar 

  44. Asante, E. A. et al. A naturally occurring variant of the human prion protein completely prevents prion disease. Nature 522, 478–481 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Mead, S. et al. Genetic risk factors for variant Creutzfeldt-Jakob disease: a genome-wide association study. Lancet Neurol. 8, 57–66 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  46. Mead, S. et al. Genome-wide association study in multiple human prion diseases suggests genetic risk factors additional to PRNP. Hum. Mol. Genet. 21, 1897–1906 (2012).

    Article  PubMed  CAS  Google Scholar 

  47. Sanchez-Juan, P. et al. A genome wide association study links glutamate receptor pathway to sporadic Creutzfeldt-Jakob disease risk. PLoS ONE 10, e0123654 (2014).

    Article  PubMed  CAS  Google Scholar 

  48. Minikel, E. V. et al. Quantifying prion disease penetrance using large population control cohorts. Sci. Transl Med. 8, 322ra9 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Xu, J. et al. Gain of function of mutant p53 by coaggregation with multiple tumor suppressors. Nat. Chem. Biol. 7, 285–295 (2011).

    Article  PubMed  CAS  Google Scholar 

  50. Levy, C. B. et al. Co-localization of mutant p53 and amyloid-like protein aggregates in breast tumors. Int. J. Biochem. Cell Biol. 43, 60–64 (2011).

    Article  PubMed  CAS  Google Scholar 

  51. Forget, K. J., Tremblay, G. & Roucou, X. p53 aggregates penetrate cells and induce the co-aggregation of intracellular p53. PLoS ONE 8, e69242 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Ghosh, S. et al. p53 amyloid formation leading to its loss of function: implications in cancer pathogenesis. Cell Death Differ. 24, 1784–1798 (2017).

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  53. Alexandrova, E. M. et al. Improving survival by exploiting tumour dependence on stabilized mutant p53 for treatment. Nature 523, 352–356 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Mukherjee, A. et al. Induction of IAPP amyloid deposition and associated diabetic abnormalities by a prion-like mechanism. J. Exp. Med. 214, 2591–2610 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Murakami, T., Ishiguro, N. & Higuchi, K. Transmission of systemic AA amyloidosis in animals. Vet. Pathol. 51, 363–371 (2014).

    Article  PubMed  CAS  Google Scholar 

  56. Watts, J. C. et al. Transmission of multiple system atrophy prions to transgenic mice. Proc. Natl Acad. Sci. USA 110, 19555–19560 (2013). This study demonstrates that α-synuclein aggregates are transmissible to mice expressing a human aggregation-prone form of α-synuclein.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Prusiner, S. B. et al. Evidence for α-synuclein prions causing multiple system atrophy in humans with parkinsonism. Proc. Natl Acad. Sci. USA 112, E5308–E5317 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Sigurdson, C. J. et al. A molecular switch controls interspecies prion disease transmission in mice. J. Clin. Invest. 120, 2590–2599 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Sacino, A. N. et al. Non-prion-type transmission in A53T α-synuclein transgenic mice: a normal component of spinal homogenates from naïve non-transgenic mice induces robust α-synuclein pathology. Acta Neuropathol. 131, 151–154 (2016).

    Article  PubMed  CAS  Google Scholar 

  60. Kurowska, Z. et al. Signs of degeneration in 12-22-year old grafts of mesencephalic dopamine neurons in patients with Parkinson’s disease. J. Parkinsons Dis. 1, 83–92 (2011).

    PubMed  Google Scholar 

  61. Kordower, J. H., Chu, Y., Hauser, R. A., Freeman, T. B. & Olanow, C. W. Lewy body-like pathology in long-term embryonic nigral transplants in Parkinson’s disease. Nat. Med. 14, 504–506 (2008).

    Article  PubMed  CAS  Google Scholar 

  62. Kordower, J. H., Chu, Y., Hauser, R. A., Olanow, C. W. & Freeman, T. B. Transplanted dopaminergic neurons develop PD pathologic changes: a second case report. Mov. Disord. 23, 2303–2306 (2008).

    Article  PubMed  Google Scholar 

  63. Li, W. et al. Extensive graft-derived dopaminergic innervation is maintained 24 years after transplantation in the degenerating parkinsonian brain. Proc. Natl Acad. Sci. USA 113, 6544–6549 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  64. Li, J.-Y. et al. Lewy bodies in grafted neurons in subjects with Parkinson’s disease suggest host-to-graft disease propagation. Nat. Med. 14, 501–503 (2008).

    Article  PubMed  CAS  Google Scholar 

  65. Thal, D. R., Rüb, U., Orantes, M. & Braak, H. Phases of Aβ-deposition in the human brain and its relevance for the development of AD. Neurology 58, 1791–1800 (2002).

    Article  PubMed  Google Scholar 

  66. Meyer-Luehmann, M. et al. Exogenous induction of cerebral beta-amyloidogenesis is governed by agent and host. Science 313, 1781–1784 (2006).

    Article  PubMed  CAS  Google Scholar 

  67. Stöhr, J. et al. Purified and synthetic Alzheimer’s amyloid beta (Aβ) prions. Proc. Natl Acad. Sci. USA 109, 11025–11030 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  68. Jaunmuktane, Z. et al. Evidence for human transmission of amyloid-β pathology and cerebral amyloid angiopathy. Nature 525, 247–250 (2015).

    Article  PubMed  CAS  Google Scholar 

  69. Ritchie, D. L. et al. Amyloid-β accumulation in the CNS in human growth hormone recipients in the UK. Acta Neuropathol. 134, 221–240 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Frontzek, K., Lutz, M. I., Aguzzi, A., Kovacs, G. G. & Budka, H. Amyloid-β pathology and cerebral amyloid angiopathy are frequent in iatrogenic Creutzfeldt-Jakob disease after dural grafting. Swiss Med. Wkly 146, w14287 (2016).

    PubMed  Google Scholar 

  71. Arnold, S. E. et al. Comparative survey of the topographical distribution of signature molecular lesions in major neurodegenerative diseases. J. Comp. Neurol. 521, 4339–4355 (2013).

    Article  PubMed  Google Scholar 

  72. Audouard, E. et al. High-molecular-weight paired helical filaments from Alzheimer brain induces seeding of wild-type mouse tau into an argyrophilic 4R tau pathology in vivo. Am. J. Pathol. 186, 2709–2722 (2016).

    Article  PubMed  CAS  Google Scholar 

  73. Duyckaerts, C. et al. Neuropathology of iatrogenic Creutzfeldt-Jakob disease and immunoassay of French cadaver-sourced growth hormone batches suggest possible transmission of tauopathy and long incubation periods for the transmission of Aβ pathology. Acta Neuropathol. 135, 201–212 (2018).

    Article  PubMed  CAS  Google Scholar 

  74. Malinovska, L., Kroschwald, S. & Alberti, S. Protein disorder, prion propensities, and self-organizing macromolecular collectives. Biochim. Biophys. Acta 1834, 918–931 (2013).

    Article  PubMed  CAS  Google Scholar 

  75. Hyman, A. A., Weber, C. A. & Jülicher, F. Liquid-liquid phase separation in biology. Annu. Rev. Cell Dev. Biol. 30, 39–58 (2014).

    Article  PubMed  CAS  Google Scholar 

  76. Sonati, T. et al. The toxicity of antiprion antibodies is mediated by the flexible tail of the prion protein. Nature 501, 102–106 (2013). This study demonstrates that antibodies can be protective or toxic, depending on the recognized epitope.

    Article  PubMed  CAS  Google Scholar 

  77. Heppner, F. L. et al. Prevention of scrapie pathogenesis by transgenic expression of anti-prion protein antibodies. Science 294, 178–182 (2001). This paper introduces the novel concept that prion disease pathogenesis can be inhibited by protective PrP antibodies.

    Article  PubMed  CAS  Google Scholar 

  78. Polymenidou, M. et al. The POM monoclonals: a comprehensive set of antibodies to non-overlapping prion protein epitopes. PLoS ONE 3, e3872 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. Herrmann, U. S. et al. Prion infections and anti-PrP antibodies trigger converging neurotoxic pathways. PLoS Pathog. 11, e1004662 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Falsig, J. et al. Prion pathogenesis is faithfully reproduced in cerebellar organotypic slice cultures. PLoS Pathog. 8, e1002985 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  81. Frontzek, K. et al. Neurotoxic antibodies against the prion protein do not trigger prion replication. PLoS ONE 11, e0163601 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Yim, Y.-I. et al. The multivesicular body is the major internal site of prion conversion. J. Cell. Sci. 128, 1434–1443 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. Vella, L. J., Hill, A. F. & Cheng, L. Focus on extracellular vesicles: exosomes and their role in protein trafficking and biomarker potential in Alzheimer’s and Parkinson’s disease. Int. J. Mol. Sci. 17, 173 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  84. Gousset, K. et al. Prions hijack tunnelling nanotubes for intercellular spread. Nat. Cell Biol. 11, 328–336 (2009).

    Article  PubMed  CAS  Google Scholar 

  85. Senatore, A. et al. Mutant PrP suppresses glutamatergic neurotransmission in cerebellar granule neurons by impairing membrane delivery of VGCC α(2)δ-1 subunit. Neuron 74, 300–313 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Rodríguez, A. et al. Metabotropic glutamate receptor/phospholipase C pathway: a vulnerable target to Creutzfeldt-Jakob disease in the cerebral cortex. Neuroscience 131, 825–832 (2005).

    Article  PubMed  CAS  Google Scholar 

  87. Rodríguez, A. et al. Group I mGluR signaling in BSE-infected bovine-PrP transgenic mice. Neurosci. Lett. 410, 115–120 (2006).

    Article  PubMed  CAS  Google Scholar 

  88. Goniotaki, D. et al. Inhibition of group-I metabotropic glutamate receptors protects against prion toxicity. PLoS Pathog. 13, e1006733 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  89. Khosravani, H. et al. Prion protein attenuates excitotoxicity by inhibiting NMDA receptors. J. Gen. Physiol. 131, i5 (2008).

    Article  PubMed  Google Scholar 

  90. Laurén, J., Gimbel, D. A., Nygaard, H. B., Gilbert, J. W. & Strittmatter, S. M. Cellular prion protein mediates impairment of synaptic plasticity by amyloid-beta oligomers. Nature 457, 1128–1132 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  91. Gimbel, D. A. et al. Memory impairment in transgenic Alzheimer mice requires cellular prion protein. J. Neurosci. 30, 6367–6374 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  92. Haas, L. T., Kostylev, M. A. & Strittmatter, S. M. Therapeutic molecules and endogenous ligands regulate the interaction between brain cellular prion protein (PrPC) and metabotropic glutamate receptor 5 (mGluR5). J. Biol. Chem. 289, 28460–28477 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  93. Um, J. W. et al. Metabotropic glutamate receptor 5 is a coreceptor for Alzheimer aβ oligomer bound to cellular prion protein. Neuron 79, 887–902 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  94. Um, J. W. et al. Alzheimer amyloid-β oligomer bound to postsynaptic prion protein activates Fyn to impair neurons. Nat. Neurosci. 15, 1227–1235 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Hu, N.-W. et al. mGlu5 receptors and cellular prion protein mediate amyloid-β-facilitated synaptic long-term depression in vivo. Nat. Commun. 5, 3374 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Ostapchenko, V. G. et al. Increased prion protein processing and expression of metabotropic glutamate receptor 1 in a mouse model of Alzheimer’s disease. J. Neurochem. 127, 415–425 (2013).

    Article  PubMed  CAS  Google Scholar 

  97. Renner, M. et al. Deleterious effects of amyloid beta oligomers acting as an extracellular scaffold for mGluR5. Neuron 66, 739–754 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Hamilton, A., Esseltine, J. L., DeVries, R. A., Cregan, S. P. & Ferguson, S. S. G. Metabotropic glutamate receptor 5 knockout reduces cognitive impairment and pathogenesis in a mouse model of Alzheimer’s disease. Mol. Brain 7, 40 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Balducci, C. et al. Synthetic amyloid-beta oligomers impair long-term memory independently of cellular prion protein. Proc. Natl Acad. Sci. USA 107, 2295–2300 (2010).

    Article  PubMed  PubMed Central  Google Scholar 

  100. Kessels, H. W., Nguyen, L. N., Nabavi, S. & Malinow, R. The prion protein as a receptor for amyloid-beta. Nature 466, E3–E4 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Calella, A. M. et al. Prion protein and Abeta-related synaptic toxicity impairment. EMBO Mol. Med. 2, 306–314 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  102. Cissé, M. et al. Ablation of cellular prion protein does not ameliorate abnormal neural network activity or cognitive dysfunction in the J20 line of human amyloid precursor protein transgenic mice. J. Neurosci. 31, 10427–10431 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Aulic, S. et al. α-Synuclein amyloids hijack prion protein to gain cell entry, facilitate cell-to-cell spreading and block prion replication. Sci. Rep. 7, 10050 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  104. Ferreira, D. G. et al. α-Synuclein interacts with PrP(C) to induce cognitive impairment through mGluR5 and NMDAR2B. Nat. Neurosci. 20, 1569–1579 (2017).

    Article  PubMed  CAS  Google Scholar 

  105. Diógenes, M. J. et al. Extracellular alpha-synuclein oligomers modulate synaptic transmission and impair LTP via NMDA-receptor activation. J. Neurosci. 32, 11750–11762 (2012).

    Article  PubMed  CAS  Google Scholar 

  106. Parizek, P. et al. Similar turnover and shedding of the cellular prion protein in primary lymphoid and neuronal cells. J. Biol. Chem. 276, 44627–44632 (2001).

    Article  PubMed  CAS  Google Scholar 

  107. Yedidia, Y., Horonchik, L., Tzaban, S., Yanai, A. & Taraboulos, A. Proteasomes and ubiquitin are involved in the turnover of the wild-type prion protein. EMBO J. 20, 5383–5391 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Ma, J. & Lindquist, S. Conversion of PrP to a self-perpetuating PrPSc-like conformation in the cytosol. Science 298, 1785–1788 (2002).

    Article  PubMed  CAS  Google Scholar 

  109. Stewart, R. S., Drisaldi, B. & Harris, D. A. A transmembrane form of the prion protein contains an uncleaved signal peptide and is retained in the endoplasmic reticulum. Mol. Biol. Cell 12, 881–889 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Ma, J. & Lindquist, S. Wild-type PrP and a mutant associated with prion disease are subject to retrograde transport and proteasome degradation. Proc. Natl Acad. Sci. USA 98, 14955–14960 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Zanusso, G. et al. Proteasomal degradation and N-terminal protease resistance of the codon 145 mutant prion protein. J. Biol. Chem. 274, 23396–23404 (1999).

    Article  PubMed  CAS  Google Scholar 

  112. Jin, T. et al. The chaperone protein BiP binds to a mutant prion protein and mediates its degradation by the proteasome. J. Biol. Chem. 275, 38699–38704 (2000).

    Article  PubMed  CAS  Google Scholar 

  113. Drisaldi, B. et al. Mutant PrP is delayed in its exit from the endoplasmic reticulum, but neither wild-type nor mutant PrP undergoes retrotranslocation prior to proteasomal degradation. J. Biol. Chem. 278, 21732–21743 (2003).

    Article  PubMed  CAS  Google Scholar 

  114. Kristiansen, M. et al. Disease-associated prion protein oligomers inhibit the 26S proteasome. Mol. Cell 26, 175–188 (2007).

    Article  PubMed  CAS  Google Scholar 

  115. Kristiansen, M. et al. Disease-related prion protein forms aggresomes in neuronal cells leading to caspase activation and apoptosis. J. Biol. Chem. 280, 38851–38861 (2005).

    Article  PubMed  CAS  Google Scholar 

  116. Deriziotis, P. et al. Misfolded PrP impairs the UPS by interaction with the 20S proteasome and inhibition of substrate entry. EMBO J. 30, 3065–3077 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Moreno, J. A. et al. Sustained translational repression by eIF2α-P mediates prion neurodegeneration. Nature 485, 507–511 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Abisambra, J. F. et al. Tau accumulation activates the unfolded protein response by impairing endoplasmic reticulum-associated degradation. J. Neurosci. 33, 9498–9507 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  119. Atkin, J. D. et al. Endoplasmic reticulum stress and induction of the unfolded protein response in human sporadic amyotrophic lateral sclerosis. Neurobiol. Dis. 30, 400–407 (2008).

    Article  PubMed  CAS  Google Scholar 

  120. Devi, L. & Ohno, M. PERK mediates eIF2α phosphorylation responsible for BACE1 elevation, CREB dysfunction and neurodegeneration in a mouse model of Alzheimer’s disease. Neurobiol. Aging 35, 2272–2281 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  121. Saxena, S., Cabuy, E. & Caroni, P. A role for motoneuron subtype-selective ER stress in disease manifestations of FALS mice. Nat. Neurosci. 12, 627–636 (2009).

    Article  PubMed  CAS  Google Scholar 

  122. Hoozemans, J. J. M. et al. Activation of the unfolded protein response in Parkinson’s disease. Biochem. Biophys. Res. Commun. 354, 707–711 (2007).

    Article  PubMed  CAS  Google Scholar 

  123. Radford, H., Moreno, J. A., Verity, N., Halliday, M. & Mallucci, G. R. PERK inhibition prevents tau-mediated neurodegeneration in a mouse model of frontotemporal dementia. Acta Neuropathol. 130, 633–642 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  124. Horiuchi, M., Yamazaki, N., Ikeda, T., Ishiguro, N. & Shinagawa, M. A cellular form of prion protein (PrPC) exists in many non-neuronal tissues of sheep. J. Gen. Virol. 76, 2583–2587 (1995).

    Article  PubMed  CAS  Google Scholar 

  125. Arai, H. et al. Expression patterns of beta-amyloid precursor protein (beta-APP) in neural and nonneural human tissues from Alzheimer’s disease and control subjects. Ann. Neurol. 30, 686–693 (1991).

    Article  PubMed  CAS  Google Scholar 

  126. Gu, Y., Oyama, F. & Ihara, Y. Tau is widely expressed in rat tissues. J. Neurochem. 67, 1235–1244 (1996).

    Article  PubMed  CAS  Google Scholar 

  127. Klein, M. A. et al. A crucial role for B cells in neuroinvasive scrapie. Nature 390, 687–690 (1997).

    Article  PubMed  CAS  Google Scholar 

  128. Raeber, A. J. et al. Ectopic expression of prion protein (PrP) in T lymphocytes or hepatocytes of PrP knockout mice is insufficient to sustain prion replication. Proc. Natl Acad. Sci. USA 96, 3987–3992 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Yang, W. & Yu, S. Synucleinopathies: common features and hippocampal manifestations. Cell. Mol. Life Sci. 74, 1485–1501 (2017).

    Article  PubMed  CAS  Google Scholar 

  130. Ferrer, I., Casas, R. & Rivera, R. Parvalbumin-immunoreactive cortical neurons in Creutzfeldt-Jakob disease. Ann. Neurol. 34, 864–866 (1993).

    Article  PubMed  CAS  Google Scholar 

  131. Guentchev, M., Groschup, M. H., Kordek, R., Liberski, P. P. & Budka, H. Severe, early and selective loss of a subpopulation of GABAergic inhibitory neurons in experimental transmissible spongiform encephalopathies. Brain Pathol. 8, 615–623 (1998).

    Article  PubMed  CAS  Google Scholar 

  132. Guentchev, M., Wanschitz, J., Voigtländer, T., Flicker, H. & Budka, H. Selective neuronal vulnerability in human prion diseases. Fatal familial insomnia differs from other types of prion diseases. Am. J. Pathol. 155, 1453–1457 (1999).

    PubMed  CAS  Google Scholar 

  133. Sargent, D. et al. ‘Prion-like’ propagation of the synucleinopathy of M83 transgenic mice depends on the mouse genotype and type of inoculum. J. Neurochem. 143, 126–135 (2017).

    Article  PubMed  CAS  Google Scholar 

  134. Bu, X.-L. et al. Blood-derived amyloid-β protein induces Alzheimer’s disease pathologies. Mol. Psychiatry https://doi.org/10.1038/mp.2017.204 (2017).

  135. Glatzel, M., Heppner, F. L., Albers, K. M. & Aguzzi, A. Sympathetic innervation of lymphoreticular organs is rate limiting for prion neuroinvasion. Neuron 31, 25–34 (2001).

    Article  PubMed  CAS  Google Scholar 

  136. Prinz, M. et al. Positioning of follicular dendritic cells within the spleen controls prion neuroinvasion. Nature 425, 957–962 (2003).

    Article  PubMed  CAS  Google Scholar 

  137. Hill, A. F. et al. The same prion strain causes vCJD and BSE. Nature 389, 448–450 (1997).

    Article  PubMed  CAS  Google Scholar 

  138. Saido, T. C. et al. Dominant and differential deposition of distinct beta-amyloid peptide species, Aβ N3(pE), in senile plaques. Neuron 14, 457–466 (1995).

    Article  PubMed  CAS  Google Scholar 

  139. Schilling, S. et al. Glutaminyl cyclase inhibition attenuates pyroglutamate Abeta and Alzheimer’s disease-like pathology. Nat. Med. 14, 1106–1111 (2008).

    Article  PubMed  CAS  Google Scholar 

  140. Castegna, A. et al. Proteomic identification of nitrated proteins in Alzheimer’s disease brain. J. Neurochem. 85, 1394–1401 (2003).

    Article  PubMed  CAS  Google Scholar 

  141. Smith, M. A., Richey Harris, P. L., Sayre, L. M., Beckman, J. S. & Perry, G. Widespread peroxynitrite-mediated damage in Alzheimer’s disease. J. Neurosci. 17, 2653–2657 (1997).

    Article  PubMed  CAS  Google Scholar 

  142. Sweeney, P. et al. Protein misfolding in neurodegenerative diseases: implications and strategies. Transl Neurodegener. 6, 6 (2017).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  143. Steele, A. D. et al. Heat shock factor 1 regulates lifespan as distinct from disease onset in prion disease. Proc. Natl Acad. Sci. USA 105, 13626–13631 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  144. Baldo, B. et al. A screen for enhancers of clearance identifies huntingtin as a heat shock protein 90 (Hsp90) client protein. J. Biol. Chem. 287, 1406–1414 (2012).

    Article  PubMed  CAS  Google Scholar 

  145. Luo, W. et al. Roles of heat-shock protein 90 in maintaining and facilitating the neurodegenerative phenotype in tauopathies. Proc. Natl Acad. Sci. USA 104, 9511–9516 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  146. Labbadia, J. et al. Altered chromatin architecture underlies progressive impairment of the heat shock response in mouse models of Huntington disease. J. Clin. Invest. 121, 3306–3319 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Putcha, P. et al. Brain-permeable small-molecule inhibitors of Hsp90 prevent alpha-synuclein oligomer formation and rescue alpha-synuclein-induced toxicity. J. Pharmacol. Exp. Ther. 332, 849–857 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Hetz, C., Russelakis-Carneiro, M., Maundrell, K., Castilla, J. & Soto, C. Caspase-12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein. EMBO J. 22, 5435–5445 (2003).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  149. Yoo, B. C. et al. Overexpressed protein disulfide isomerase in brains of patients with sporadic Creutzfeldt-Jakob disease. Neurosci. Lett. 334, 196–200 (2002).

    Article  PubMed  CAS  Google Scholar 

  150. Hoshino, T. et al. Endoplasmic reticulum chaperones inhibit the production of amyloid-beta peptides. Biochem. J. 402, 581–589 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  151. Park, K.-W. et al. The endoplasmic reticulum chaperone GRP78/BiP modulates prion propagation in vitro and in vivo. Sci. Rep. 7, 44723 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  152. Hetz, C. et al. The disulfide isomerase Grp58 is a protective factor against prion neurotoxicity. J. Neurosci. 25, 2793–2802 (2005).

    Article  PubMed  CAS  Google Scholar 

  153. Glover, J. R. & Lindquist, S. Hsp104, Hsp70, and Hsp40: a novel chaperone system that rescues previously aggregated proteins. Cell 94, 73–82 (1998).

    Article  PubMed  CAS  Google Scholar 

  154. Shorter, J. & Lindquist, S. Hsp104 catalyzes formation and elimination of self-replicating Sup35 prion conformers. Science 304, 1793–1797 (2004).

    Article  PubMed  CAS  Google Scholar 

  155. Chernoff, Y. O., Lindquist, S. L., Ono, B., Inge-Vechtomov, S. G. & Liebman, S. W. Role of the chaperone protein Hsp104 in propagation of the yeast prion-like factor [psi+]. Science 268, 880–884 (1995).

    Article  PubMed  CAS  Google Scholar 

  156. Aguzzi, A., Lakkaraju, A. K. K. & Frontzek, K. Toward therapy of human prion diseases. Annu. Rev. Pharmacol. Toxicol. 58, 331–351 (2018).

    Article  PubMed  CAS  Google Scholar 

  157. Silva, J. L., De Moura Gallo, C. V., Costa, D. C. F. & Rangel, L. P. Prion-like aggregation of mutant p53 in cancer. Trends Biochem. Sci. 39, 260–267 (2014).

    Article  PubMed  CAS  Google Scholar 

  158. Whitesell, L. & Lindquist, S. L. HSP90 and the chaperoning of cancer. Nat. Rev. Cancer 5, 761–772 (2005).

    Article  PubMed  CAS  Google Scholar 

  159. Soragni, A. et al. A designed inhibitor of p53 aggregation rescues p53 tumor suppression in ovarian carcinomas. Cancer Cell 29, 90–103 (2016).

    Article  PubMed  CAS  Google Scholar 

  160. Wang, B. et al. A CNS-permeable Hsp90 inhibitor rescues synaptic dysfunction and memory loss in APP-overexpressing Alzheimer’s mouse model via an HSF1-mediated mechanism. Mol. Psychiatry 22, 990–1001 (2017).

    Article  PubMed  CAS  Google Scholar 

  161. Ansar, S. et al. A non-toxic Hsp90 inhibitor protects neurons from Aβ-induced toxicity. Bioorg. Med. Chem. Lett. 17, 1984–1990 (2007).

    Article  PubMed  CAS  Google Scholar 

  162. Diaz-Espinoza, R. et al. Treatment with a non-toxic, self-replicating anti-prion delays or prevents prion disease in vivo. Mol. Psychiatry 23, 777–788 (2018).

    Article  PubMed  CAS  Google Scholar 

  163. Abeliovich, A. et al. Mice lacking alpha-synuclein display functional deficits in the nigrostriatal dopamine system. Neuron 25, 239–252 (2000).

    Article  PubMed  CAS  Google Scholar 

  164. Zheng, H. et al. β-Amyloid precursor protein-deficient mice show reactive gliosis and decreased locomotor activity. Cell 81, 525–531 (1995).

    Article  PubMed  CAS  Google Scholar 

  165. Soto, C. et al. Reversion of prion protein conformational changes by synthetic beta-sheet breaker peptides. Lancet 355, 192–197 (2000).

    Article  PubMed  CAS  Google Scholar 

  166. Nilsson, K. P. R. et al. Structural typing of systemic amyloidoses by luminescent-conjugated polymer spectroscopy. Am. J. Pathol. 176, 563–574 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  167. Margalith, I. et al. Polythiophenes inhibit prion propagation by stabilizing prion protein (PrP) aggregates. J. Biol. Chem. 287, 18872–18887 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  168. Sigurdson, C. J. et al. Prion strain discrimination using luminescent conjugated polymers. Nat. Methods 4, 1023–1030 (2007).

    Article  PubMed  CAS  Google Scholar 

  169. Herrmann, U. S. et al. Structure-based drug design identifies polythiophenes as antiprion compounds. Sci. Transl Med. 7, 299ra123 (2015).

    Article  PubMed  CAS  Google Scholar 

  170. Frenzel, A., Schirrmann, T. & Hust, M. Phage display-derived human antibodies in clinical development and therapy. mAbs 8, 1177–1194 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  171. Polymenidou, M. et al. Humoral immune response to native eukaryotic prion protein correlates with anti-prion protection. Proc. Natl Acad. Sci. USA 101(Suppl. 2), 14670–14676 (2004).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  172. Falsig, J. & Aguzzi, A. The prion organotypic slice culture assay — POSCA. Nat. Protoc. 3, 555–562 (2008).

    Article  PubMed  CAS  Google Scholar 

  173. Zhu, C. et al. A neuroprotective role for microglia in prion diseases. J. Exp. Med. 213, 1047–1059 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  174. Kranich, J. et al. Engulfment of cerebral apoptotic bodies controls the course of prion disease in a mouse strain-dependent manner. J. Exp. Med. 207, 2271–2281 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  175. Sevigny, J. et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature 537, 50–56 (2016). This paper describes the human antibody aducanumab, the first therapeutic shown to affect the cognitive decline in AD patients.

    Article  PubMed  CAS  Google Scholar 

  176. Cummings, J. L., Morstorf, T. & Zhong, K. Alzheimer’s disease drug-development pipeline: few candidates, frequent failures. Alzheimers Res. Ther. 6, 37 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Price, J. L. & Morris, J. C. Tangles and plaques in nondemented aging and ‘preclinical’ Alzheimer’s disease. Ann. Neurol. 45, 358–368 (1999).

    Article  PubMed  CAS  Google Scholar 

  178. Jack, C. R. et al. Serial PIB and MRI in normal, mild cognitive impairment and Alzheimer’s disease: implications for sequence of pathological events in Alzheimer’s disease. Brain 132, 1355–1365 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  179. Luk, K. C. et al. Pathological α-synuclein transmission initiates Parkinson-like neurodegeneration in nontransgenic mice. Science 338, 949–953 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Lundmark, K. et al. Transmissibility of systemic amyloidosis by a prion-like mechanism. Proc. Natl Acad. Sci. USA 99, 6979–6984 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  181. Burns, T. C., Li, M. D., Mehta, S., Awad, A. J. & Morgan, A. A. Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models. Eur. J. Pharmacol. 759, 101–117 (2015).

    Article  PubMed  CAS  Google Scholar 

  182. Zanusso, G., Monaco, S., Pocchiari, M. & Caughey, B. Advanced tests for early and accurate diagnosis of Creutzfeldt-Jakob disease. Nat. Rev. Neurol. 12, 325–333 (2016).

    Article  PubMed  CAS  Google Scholar 

  183. Edgeworth, J. A. et al. Detection of prion infection in variant Creutzfeldt-Jakob disease: a blood-based assay. Lancet 377, 487–493 (2011).

    Article  PubMed  CAS  Google Scholar 

  184. Jackson, G. S. et al. A highly specific blood test for vCJD. Blood 123, 452–453 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  185. Saá, P., Castilla, J. & Soto, C. Presymptomatic detection of prions in blood. Science 313, 92–94 (2006).

    Article  PubMed  CAS  Google Scholar 

  186. Colby, D. W. et al. Prion detection by an amyloid seeding assay. Proc. Natl Acad. Sci. USA 104, 20914–20919 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  187. Atarashi, R. et al. Simplified ultrasensitive prion detection by recombinant PrP conversion with shaking. Nat. Methods 5, 211–212 (2008).

    Article  PubMed  CAS  Google Scholar 

  188. Atarashi, R. et al. Ultrasensitive human prion detection in cerebrospinal fluid by real-time quaking-induced conversion. Nat. Med. 17, 175–178 (2011).

    Article  PubMed  CAS  Google Scholar 

  189. Orrú, C. D. et al. Rapid and sensitive RT-QuIC detection of human Creutzfeldt-Jakob disease using cerebrospinal fluid. mBio 6, e02451–14 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  190. Concha-Marambio, L. et al. Detection of prions in blood from patients with variant Creutzfeldt-Jakob disease. Sci. Transl Med. 8, 370ra183 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  191. Bougard, D. et al. Detection of prions in the plasma of presymptomatic and symptomatic patients with variant Creutzfeldt-Jakob disease. Sci. Transl Med. 8, 370ra182 (2016).

    Article  PubMed  CAS  Google Scholar 

  192. Ito, D., Hatano, M. & Suzuki, N. RNA binding proteins and the pathological cascade in ALS/FTD neurodegeneration. Sci. Transl Med. 9, eaah5436 (2017).

    Article  PubMed  Google Scholar 

  193. Jackson, W. S. Selective vulnerability to neurodegenerative disease: the curious case of Prion Protein. Dis. Model. Mech. 7, 21–29 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  194. Pettersen, E. F. et al. UCSF Chimera — a visualization system for exploratory research and analysis. J. Comput. Chem. 25, 1605–1612 (2004).

    Article  PubMed  CAS  Google Scholar 

  195. Aguzzi, A., Baumann, F. & Bremer, J. The prion’s elusive reason for being. Annu. Rev. Neurosci. 31, 439–477 (2008).

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

C.S. is the recipient of a Marie Curie Individual Fellowship. A.A. is the recipient of an advanced grant of the European Research Council and grants from the Swiss National Research Foundation, the Clinical Research Priority Programs ‘Small RNAs’ and ‘Human Haemato-Lymphatic Diseases’ of the University of Zurich and SystemsX.ch. Molecular graphics and analyses were performed with the University of California, San Francisco (UCSF) Chimaera package. Chimaera is developed by the Resource for Biocomputing, Visualization and Informatics at UCSF (supported by NIGMS P41-GM103311).

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Nature Reviews Genetics thanks E. Biasini, C. Soto and the other, anonymous reviewer(s) for their contribution to the peer review of this work.

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  1. Institute of Neuropathology, University of Zurich, Zurich, Switzerland

    Claudia Scheckel & Adriano Aguzzi

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Adriano Aguzzi is a founder and director of Mabylon Inc., a company devoted to the development of human antibodies for treating intractable diseases, including neurodegeneration. The authors are not aware of any other affiliations, memberships, funding or financial holdings that might be perceived as affecting the objectivity of this Review.

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Glossary

Prion diseases

(PrDs). A group of diseases caused by an infectious protein, which includes genetic, acquired and sporadic forms. PrDs have an overall incidence of one to two cases per million individuals per year.

Prion

The agent causing transmissible spongiform encephalopathies. As originally defined, the term does not have structural implications other than that a protein is an essential component. Although it is now generally accepted that the prion consists largely of the pathological aggregate of the prion protein, PrPSc, prions are defined as a biological activity rather than a physical entity. Hence, they can be measured by activity assays rather than by quantitating PrPSc.

Aggregates

In the context of this Review, the term ‘aggregate’ is used to denote the coalescence of misfolded proteins into highly ordered structures, typically resulting in the formation of fibrils.

Protein misfolding disorders

(PMDs). Disorders that are characterized by protein aggregates, which induce neurodegeneration if present in the brain.

Propagon

The minimal propagating unit of a misfolded protein, defined by its capacity to self-replicate in vitro and/or in vivo. A propagon that can transmit from a host individual to another individual is called a prion.

Prionoids

Protein aggregates that can propagate and spread between cells but for which transmissibility between individuals has not yet been demonstrated.

Polymorphisms

Any sites in the DNA sequence that are present in the general population in more than one state.

Penetrance

The percentage of individuals with a mutation who exhibit clinical symptoms. Most PRNP mutations are highly penetrant, meaning that most individuals with PRNP mutations develop prion disease.

Prion strains

Entities associated with distinct biochemical and neuropathological profiles, translating into a spectrum of incubation periods and clinical signs. Crucially, strain-specific traits are stable across serial transmission between isogenic hosts, indicating that they are encoded by the prion itself. Distinct structural assemblies of chemically identical pathological aggregates of the prion protein, PrPSc, are thought to underlie strain-ness.

Phase demixing

Process of membrane-less compartmentalization. Spontaneous demixing of two coexisting phases is driven by intermolecular interactions, a propensity that seems to be particularly high for proteins with low-complexity domains.

Excitotoxicity

Neuronal overstimulation caused by increased levels of the excitatory neurotransmitter glutamate leading to calcium overload and mitochondrial dysfunction and ultimately to neuronal cell death and memory loss.

Parabiosis

Surgical technique to anatomically connect two individuals. The shared circulatory system between the individuals allows specific factors to be assessed for their involvement in regulating physiological functions, behaviour and disease pathogenesis.

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Scheckel, C., Aguzzi, A. Prions, prionoids and protein misfolding disorders. Nat Rev Genet 19, 405–418 (2018). https://doi.org/10.1038/s41576-018-0011-4

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